TY - JOUR
T1 - Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease
AU - Celorrio, Marta
AU - Fernández-Suárez, Diana
AU - Rojo-Bustamante, Estefanía
AU - Echeverry-Alzate, Víctor
AU - Ramírez, María J.
AU - Hillard, Cecilia J.
AU - López-Moreno, José A.
AU - Maldonado, Rafael
AU - Oyarzábal, Julen
AU - Franco, Rafael
AU - Aymerich, María S.
N1 - Funding Information:
This work was supported by the projects PI14/02070 and SAF2012-39875-C02-01 from the Spanish Government (Plan estatal I+D+I 2013–2016 and ISCIII-FEDER), Fundación Gangoiti and the UTE-project/Foundation for Applied Medical Research ( FIMA ). Estefanía Rojo is supported by a predoctoral fellowship from Colfuturo. Partial support was also provided by the Research and Education Program of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5 weeks. URB597 (1 mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.
AB - Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5 weeks. URB597 (1 mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.
KW - CB receptor
KW - CB receptor
KW - Endocannabinoid system
KW - FAAH
KW - Parkinson's disease
KW - URB597
UR - http://www.scopus.com/inward/record.url?scp=84977659397&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2016.06.010
DO - 10.1016/j.bbi.2016.06.010
M3 - Article
C2 - 27318096
AN - SCOPUS:84977659397
SN - 0889-1591
VL - 57
SP - 94
EP - 105
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -